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Objective Thalamus is essential in processing of sensory information. This study explored the associations between thalamic volume and intra-thalamic metabolites and associations to clinical and experimental characteristics of sensory function in adults with diabetic polyneuropathy. Methods 48 adults with type 1 diabetes and confirmed distal symmetric peripheral neuropathy (DPSN) and 28 healthy controls participated in a cross-sectional study and underwent a brain magnetic resonance imaging scan. Estimates for thalamic volume were extracted using voxel-based morphometry and intra-thalamic N-acetylaspartate/creatine (NAA/cre) levels were assessed by magnetic resonance spectroscopy. Associations between thalamic volume and clinical measures, quantitative sensory testing and neuropathic phenotype were explored. Results In diabetes, reduced gray matter volume was identified including bilateral thalamus (all p≤0.001) in comparison to healthy participants. Thalamic volume estimates were positively associated to intra-thalamic NAA/cre (r=0.4; p=0.006), however not to diabetes duration (p=0.5), severity of DSPN (p=0.7), or presence of pain (p=0.3). Individuals with the lowest thalamic volume had greatest loss of protective sensation (light touch using von Frey-like filaments, p=0.037) and highest pain tolerance to electric stimulation (tetanic stimulation, p=0.008) compared to individuals with the highest thalamic volume. Conclusions In this cohort with type 1 diabetes and severe DSPN, thalamic atrophy was present and associated with reduced NAA/cre, indicating thalamic structural loss and dysfunction. Thalamic atrophy was associated to reduced sensory function involving large fiber neuropathy and sensation to tetanic stimulation that may reflect synaptic transmission. This may ultimately contribute to the current understanding of the pathophysiology behind the perception changes evident in DSPN.

OBJECTIVE The vast number of antihyperglycemic medications and growing amount of evidence make clinical decision making difficult. The aim of this study was to investigate the safety of antihyperglycemic dual and triple therapies for type 2 diabetes management with respect to major adverse cardiovascular events, severe hypoglycemia, and all-cause mortality in a real-life clinical setting. RESEARCH DESIGN AND METHODS Cox regression models were constructed to analyze 20 years of data from the Danish National Patient Registry with respect to effect of the antihyperglycemic therapies on the three end points. RESULTS A total of 66,807 people with type 2 diabetes were treated with metformin (MET) plus a combination of second- and third-line therapies. People on MET plus sulfonylurea (SU) had the highest risk of all end points, except for severe hypoglycemia, for which people on MET plus basal insulin (BASAL) had a higher risk. The lowest risk of major adverse cardiovascular events was seen for people on a regimen including a glucagon-like peptide 1 (GLP-1) receptor agonist. People treated with MET, GLP-1, and BASAL had a lower risk of all three end points than people treated with MET and BASAL, especially for severe hypoglycemia. The lowest risk of all three end points was, in general, seen for people treated with MET, sodium–glucose cotransporter 2 inhibitor, and GLP-1. CONCLUSIONS Findings from this study do not support SU as the second-line treatment choice for patients with type 2 diabetes. Moreover, the results indicate that adding a GLP-1 in people treated with MET and BASAL could be considered, especially if those people suffer from severe hypoglycemia.

Aim: To develop a protocol and set of purpose-built psychometric PRO evaluation questionnaires for a national multi-sector study to evaluate feasibility, acceptability, validity, barriers, facilitators and perceived value of the National Danish PRO diabetes intervention (PRO diabetes questionnaire and dialogue tool) in Denmark. Methods: The protocol was designed through a participatory process with People With Diabetes (PWD), multi-disciplinary representatives of diabetes centres and municipality diabetes rehabilitation centres from 3 regions of Denmark. Hypotheses and assessment tools were guided by formative qualitative research. The intervention involved that PWD fill out the PROM prior to their visit and the Health Care Professional (HCP) uses a PRO IT dialogue tool to collaboratively evaluate needs and plan care. Results: The pragmatic mixed-methods study protocol involved hypothesis testing and exploratory research: 1) PRO-DIA-READY Scales for Clinic and HCP PRO-Diabetes Readiness (incl. structural/process indicators of person-centred care). 2) 6-item PRO-EVAL-P Scale completed by PWD after the PROM. 3) 8-item PROCON-EVAL-HCP and 13-item PROCON-EVAL-PWD scales completed by HCPs and PWD after the visit, 4) Clinician rating scales of PROM validity 5) Semi-structured interview/group workshop guides for PWD, Caregivers (CG), multi-disciplinary HCPs, and administrators based on RE-AIM: Reach, Effectiveness, Adoption, Implementation and Maintenance, 6) HCP/PWD Follow-Up Impact Questionnaires (incl. active participation, person-centred care, care utilisation and outcomes). Newly designed evaluation scales were analyzed psychometrically. Conclusions: A protocol and new psychometric assessment tools for evaluation of validity, readiness, acceptability and impact of PRO in diabetes care were developed and successfully applied in large scale in Denmark. The new tools are available for comparative PRO research studies. Disclosure S.E. Skovlund: None. L. Boel: None. N.C. Balk-Møller: None. P.M. Højholt: None. D.B. Berthelsen: None. C. Glümer: None. H. Perrild: None. D.M. Hessler: Consultant; Self; Eli Lilly and Company. S.H. kaplan: None. P.O. Jakobsen: None. N. Ejskjaer: None. Funding Danish Health Data Board

BACKGROUND: Glucagon-like peptide-1 receptor agonists, such as liraglutide, reduce hyperglycaemia and induce weight loss and are used as a treatment in diabetes. However, common adverse effects include nausea, loss of appetite and prolonged gastric emptying. It is not known whether these changes are centrally generated or if liraglutide alters the enteric motility.OBJECTIVE: To investigate the effects of liraglutide on gastrointestinal function and symptoms.METHODS: A total of 48 adults with type 1 diabetes and confirmed distal symmetric polyneuropathy were randomised to receive liraglutide 1.8 mg/day or placebo for 26 weeks. Regional transit times and motility indexes were assessed with a wireless motility capsule, whereas symptoms were evaluated using the validated gastroparesis cardinal symptom index.RESULTS: Liraglutide treatment reduced large bowel transit time (31.7%, p = 0.04) and decreased motility index (6.1%, p = 0.04) compared to placebo, whereas the groups did not differ in gastric emptying or small-bowel transit times. Liraglutide increased postprandial fullness with 29% (p = 0.01). Increased small bowel transit time was associated with decreased bloating (p = 0.008).CONCLUSION: Liraglutide accelerates large bowel transit and decreases motility index, which may indicate better coordination of propulsive motility. This potentially improves the function of the enteric nervous system, leading to normalised colonic function and positive effects in type 1 diabetes.

OBJECTIVE: Distal symmetrical polyneuropathy (DSPN) is a severe common long-term complication of type 1 diabetes caused by impaired sensory-motor nerve function. As chronic low-grade inflammation may be involved in the pathogenesis of DSPN, we investigated the circulating levels of inflammatory markers in individuals with type 1 diabetes with and without DSPN. Furthermore, we determined to what extent these factors correlated with different peripheral sensory nerve functions.DESIGN: Cross-sectional study.PATIENTS: The study included 103 individuals with type 1 diabetes with (n = 50) and without DSPN (n = 53) as well as a cohort of healthy controls (n = 21).MEASUREMENTS: Circulating levels of various inflammatory markers (cytokines, chemokines and soluble adhesion molecules) were determined in serum samples by Luminex multiplexing technology. Peripheral sensory nerve testing, for example vibration, tactile and thermal perception, was assessed by standardized procedures.RESULTS: The cytokines IL-1α, IL-4, IL-12p70, IL-13, IL-17A and TNF-α; the chemokine MCP-1; and the adhesion molecule E-selectin were significantly increased in individuals with type 1 diabetes with DSPN compared to those without DSPN (P < .001). These observations were independent of age, sex, BMI, disease duration and blood pressure. Additionally, higher serum concentrations of cytokines and chemokines were associated with higher vibration and tactile perception thresholds, but not with heat tolerance threshold.CONCLUSIONS: Individuals with type 1 diabetes and concomitant DSPN display higher serum levels of several inflammatory markers. These findings support that systemic low-grade inflammation may play a role in the pathogenesis of DSPN.

BACKGROUND: Although gastrointestinal (GI) symptoms are common in diabetes, they frequently do not correlate with measurable sensorimotor abnormalities. The wireless motility capsule (WMC) measures pressure, temperature, and pH as it traverses the GI tract wherefrom transit times and motility indices are derived. The aim was to investigate whether GI symptoms correlate with changes in (a) segmental transit times, (b) segmental motility index, (c) cardiac vagal tone, or (d) presence/absence of peripheral neuropathy in type 1 diabetes.METHODS: Gastrointestinal symptoms in 104 participants with type 1 diabetes were measured using Gastroparesis Cardinal Symptoms Index and Gastrointestinal Symptom Rating Scale. All underwent standardized WMC investigation measuring segmental transit time and motility. Cardiac vagal tone and presence of peripheral neuropathy were measured using electrocardiographic and nerve conduction velocity testing.KEY RESULTS: Colonic transit time was correlated with postprandial fullness (P = .01) and constipation (P = .03), while decreased colonic motility index was correlated with diarrhea (P = .01) and decreased bloating (P < .05). Symptoms were not correlated with gastric or small bowel transit time or motility index. In participants with low cardiac vagal tone, gastric motility index (P < .01) and colonic transit time (P < .05) were increased, but not in those with peripheral neuropathy. Abdominal pain was decreased with both peripheral neuropathy (P = .04) and decreased cardiac vagal tone (P = .02).CONCLUSIONS AND INFERENCES: This study supports the rationale for whole gut investigation, using not only transit times but incorporating contractility indices as well. Furthermore, a decreased parasympathetic modulation and an increased hyposensate state appear to be present in type 1 diabetes.

Aims We hypothesized that adults with type 1 diabetes and severe polyneuropathy have alterations in neuronal transmission at different anatomical levels. The aims were to investigate upstream sensory neuronal activation in terms of peripheral, spinal, precortical, and cortical transmission. Methods 48 participants with type-1 diabetes and polyneuropathy, and 21 age-matched healthy participants were included. Electrophysiological median nerve recordings were used to analyze peripheral transmission at Erb's point (P9-N11); spinal evoked potentials at Cv7 (P11-N14); subcortical evoked potentials at Oz (N14-P18); early cortical evoked potentials at CP5 (N20-P22); late cortical evoked potentials at C1 (N60-P80) and estimated cortical inter-peak latencies as measures of central conduction time. Results In comparison to healthy, the presence of diabetes prolonged peripheral transmission at P9 and N11 (+0.49 ms, p = .000; +0.47 ms, p = .04, respectively), early cortical evoked potentials at CP5: N20 (+2.41 ms, p = .003) and P22 (+5.88 ms, p = .001) and cortical potentials at C1: N60 (+39.08 ms, p = .001) and P80 (+54.55 ms, p = .000) and central conduction time. Decreased amplitudes were shown peripherally (−2.13 μV, p = .000), spinally (−0.57 μV, p = .005) and pre-cortically (−0.22 μV, p = .004). In both healthy and people with diabetes increased central conduction time were associated with decreased parasympathetic tone (ρ = −0.52, p = .027; ρ = −0.35, p = .047, respectively). Conclusion Neuronal afferent transmission and brain responses were significantly impaired in diabetes and the presence of prolonged central conduction time is indicative of severe extensive neuronal damage. Trial registry number: EUDRA CT: 2013-004375-12; clinicaltrials.gov : NCT02138045 .

Aim: To develop a multi-dimensional Patient Reported Outcomes (PRO) questionnaire to improve person-centered care for type 1 and 2 diabetes across sectors in Denmark. Methodology: A stepwise cross-regional multi-stakeholder multi-disciplinary co-development process was undertaken: 1) Patient-important PRO domains for value based diabetes care defined (ADA 2018), 2) Multi-sector strategy for active use of PRO to benefit People With Diabetes (PWD) and care quality 3) Conceptual measurement model and psychometric methodological foundation, 4) Literature review and mapping of PRO items/scales 5) Iterative item selection/testing and design of PRO dialogue tool 7) Qualitative, clinical and psychometric evaluation. Results: The final e-PRO questionnaire (53-78 items) consisted of pre-existing/adapted items (from e.g., WHO-5, PROMIS-10, MDI, DSC-R) and newly developed global essence domain and single items covering: General health, social support, life stress, psychological well-being, symptom distress (neuropathic pain, heart, gastro-intestinal, sexual, sleep, fatigue, foot problems), diabetes well-being, worries, limitations and support, self-care, lifestyle and technology confidence, wishes for support, confidence in care access, medicine burden and satisfaction, blood sugar regulation (stability, moderate/severe hypoglycemia), preferred topics for next visit. Workshops and selective item testing (n=85) supported item acceptability and content coverage. A novel web dialogue tool with algorithms/resources to enable PWD and providers to interpret and follow-up on each PRO output was designed as part of the project. Conclusions: A systematic collaborative process led to a new PRO questionnaire and dialogue tool for use in routine diabetes care. Research is now ongoing to validate scoring and evaluate benefits of real-world use of intervention for PWD, clinicians and payers. Disclosure S.E. Skovlund: Stock/Shareholder; Self; Novo Nordisk A/S. L. Nørgaard: None. S. Stefansen: None. T. Honnens de Lichtenberg: None. L. Troelsen: None. A. Pietraszek: None. P.H. Kjær: None. H. Ravn Larsen: None. P.O. Jakobsen: None. N. Ejskjaer: None. Funding Danish Health Care System

Aims: Emerging evidence shows, that distal symmetric peripheral neuropathy (DSPN) also involves alterations in the central nervous system. Hence, the aims were to investigate brain metabolites in white matter of adults with diabetes and DSPN, and to compare any cerebral disparities with peripheral nerve characteristics. Methods: In type 1 diabetes, brain metabolites of 47 adults with confirmed DSPN were compared with 28 matched healthy controls using proton magnetic resonance spectroscopy (H-MRS) in the parietal region including the sensorimotor fiber tracts. Results: Adults with diabetes had 9.3% lower ratio of N-acetylaspartate/creatine (NAA/cre) in comparison to healthy (p < 0.001). Lower NAA/cre was associated with lower sural (p = 0.01) and tibial (p = 0.04) nerve amplitudes, longer diabetes duration (p = 0.03) and higher age (p = 0.03). In addition, NAA/cre was significantly lower in the subgroup with proliferative retinopathy as compared to the subgroup with non-proliferative retinopathy (p = 0.02). Conclusions: The association to peripheral nerve dysfunction, indicates concomitant presence of DSPN and central neuropathies, supporting the increasing recognition of diabetic neuropathy being, at least partly, a disease leading to polyneuropathy. Decreased NAA, is a potential promising biomarker of central neuronal dysfunction or loss, and thus may be useful to measure progression of neuropathy in diabetes or other neurodegenerative diseases.

BACKGROUND: A large number of adults with long-term type 1 diabetes are affected by symmetrical peripheral neuropathy. These complications increase socioeconomic expenses and diminish the individual quality of life. The 36-Item Short Form Health Survey (SF-36) is a generic patient reported questionnaire, measuring mental and physical health related quality of life. We hypothesized that diabetic neuropathy would decrease physical and mental quality of life measured with SF-36, and that clinical appearance may be associated with the decline.AIM: To investigate if diabetic neuropathy would decrease physical and mental quality of life measured with SF-36, and if clinical appearance may be associated with the decline.METHODS: Forty-eight adults [age 50 ± 9 years, 10 females, disease duration 32 (14-51) years] with verified diabetic symmetrical peripheral neuropathy and 21 healthy participants (age 51 ± 6 years, 6 females) underwent standardised nerve conduction testing and completed the SF-36 questionnaire. Furthermore, disease duration, number of comorbidities, both diabetes related and nondiabetes related, vibration perception threshold, number of hypoglycaemic events, HbA1c and administration way of insulin was notified.RESULTS: In comparison to healthy subjects, patients' mental composite score was not significantly diminished (51.9 ± 8.9 vs 53.1 ± 5.5, P = 0.558), while the physical composite score was (46.3 ± 11.7 vs 54.6 ± 3.3, P = 0.002). As expected, the overall physical health related symptoms in patients were associated to total number of comorbidities (P < 0.0001), comorbidities relation to diabetes (P = 0.0002) and HbA1c (P = 0.005) as well as comorbidities not related to diabetes (P = 0.0006).CONCLUSION: The finding of this study emphasises the importance of focusing on quality of life in adults with diabetes and especially in those with multiple comorbidities as well as the possibility of HbA1c as a biomarker for severe complication.

AIMS: Type 1 diabetes can be complicated with neuropathy that involves immune-mediated and inflammatory pathways. Glucagon-like peptide-1 receptor agonists such as liraglutide, have shown anti-inflammatory properties, and thus we hypothesized that long-term treatment with liraglutide induced diminished inflammation and thus improved neuronal function.METHODS: The study was a randomized, double-blinded, placebo-controlled trial of adults with type 1 diabetes and confirmed symmetrical polyneuropathy. They were randomly assigned (1:1) to receive either liraglutide or placebo. Titration was 6 weeks to 1.2-1.8 mg/d, continuing for 26 weeks. The primary endpoint was change in latency of early brain evoked potentials. Secondary endpoints were changes in proinflammatory cytokines, cortical evoked potential, autonomic function and peripheral neurophysiological testing.RESULTS: Thirty-nine patients completed the study, of whom 19 received liraglutide. In comparison to placebo, liraglutide reduced interleukin-6 (-22.6%; 95% confidence interval [CI]: -38.1, -3.2; P = .025) with concomitant numerical reductions in other proinflammatory cytokines. However neuronal function was unaltered at the central, autonomic or peripheral level. Treatment was associated with -3.38 kg (95% CI: -5.29, -1.48; P < .001] weight loss and a decrease in urine albumin/creatinine ratio (-40.2%; 95% CI: -60.6, -9.5; P = .02).CONCLUSION: Hitherto, diabetic neuropathy has no cure. Speculations can be raised whether mechanism targeted treatment, e.g. lowering the systemic level of proinflammatory cytokines may lead to prevention or treatment of the neuroinflammatory component in early stages of diabetic neuropathy. If ever successful, this would serve as an example of how fundamental mechanistic principles are translated into clinical practice similar to those applied in the cardiovascular and nephrological clinic.

Aim: To identify a minimal set of patient-reported (PRO) domains for use in value-based diabetes care in Denmark. Methodology: A structured mixed-methods research protocol was applied to ensure an evidence-based approach to involvement of people with diabetes in the identification of patient-centered outcome domains. 20 people with diabetes and 4 caregivers of people with diabetes selected for representativeness in age, gender, type of therapy, duration of diabetes, type of diabetes, and disease burden were recruited for qualitative research and co-creation to examine 1) psychological, physical and social impacts of diabetes and desired outcomes of treatment, 2) dis-utilities of therapy and 3) factors enabling sustainability in line with the value based care model. Qualitative research based on interviews, structured focus group and co-creation workshop sessions together with desk research on patient, clinical, health economic, and societal relevance of identified domains informed the final identification of domains by a multi-disciplinary and multi-sector working group using strict criteria of patient importance, clinical relevance and applicability, measurability and mutability. Results: The following PRO domains were selected to complement the clinical outcome domains: Self-reported health, psychological well-being, symptom burden (e.g., sleep, sexual dysfunction, complications), multi-faceted impact of diabetes on life including diabetes distress, treatment burden and impacts of hypoglycemia, and specific indicators of care confidence, quality and diabetes self-care ability. Conclusions: The assessment of patient-important outcomes for value based diabetes care in Denmark require the implementation of PRO questionnaires in standard diabetes care. Disclosure S.E. Skovlund: None. L. Troelsen: None. M. Dømgaard: None. P.O. Jakobsen: None. N. Ejskjaer: None.

BACKGROUND: The pathogenesis of diabetic polyneuropathy involves vascular, metabolic, immune-mediated and inflammatory pathways. Glucagon-like-peptide-1 receptor agonists, such as liraglutide, have shown anti-inflammatory properties. We hypothesised that liraglutide would diminish systemic and neuronal inflammation and exert a neuroregenerative/protective effect. METHODS: We performed a randomised, double-blinded, placebo-controlled trial at Aalborg University Hospital. Adults with type 1 diabetes, HbA1c >6·5 (48%) and confirmed severe sensorimotor neuropathy, were randomly assigned (1:1) to receive liraglutide/placebo. The intervention was titrated over 6 weeks to 1·2-1·8 mg/day, and continued for 26 weeks. The primary endpoint was the change in early brain activation assessed as latency of the N20-P22 evoked brain potentials. Secondary outcomes were changes in systemic pro-inflammatory cytokines and macrophage markers (IL1s, TNF-α, IL6, IL-8, IL-10, sCD163 and sCD206), sub- and late cortical activation, measures of autonomic function and peripheral neurophysiological testing. Tertiary outcomes were alterations in weight, HbA1c, blood pressure and insulin utilisation. FINDINGS: 48 patients were enrolled of which 27 were randomised to liraglutide and 21 to placebo. In comparison to placebo, 26 weeks treatment with liraglutide reduced IL-6 (-22·6% [95%CI:-38·1;-3·2,p=0·025] with numerical reductions in other pro-inflammatory cytokines and macrophage markers but failed to show any neuroregenerative/protective effect on central, autonomic or peripheral neuropathies. Furthermore, treatment was associated with -3·38% [95%CI:-5·29;-1·48,p

AIMS/HYPOTHESIS: We hypothesised that type 1 diabetic patients with established diabetic sensorimotor polyneuropathy (DSPN) would have segmental and/or pan-enteric dysmotility in comparison to healthy age-matched controls. We aimed to investigate the co-relationships between gastrointestinal function, degree of DSPN and clinical symptoms.METHODS: An observational comparison was made between 48 patients with DSPN (39 men, mean age 50 years, range 29-71 years), representing the baseline data of an ongoing clinical trial (representing a secondary analysis of baseline data collected from an ongoing double-blind randomised controlled trial investigating the neuroprotective effects of liraglutide) and 41 healthy participants (16 men, mean age 49 years, range 30-78) who underwent a standardised wireless motility capsule test to assess gastrointestinal transit. In patients, vibration thresholds, the Michigan Neuropathy Screening Instrument and Patient Assessment of Upper Gastrointestinal Symptom questionnaires were recorded.RESULTS: Compared with healthy controls, patients showed prolonged gastric emptying (299 ± 289 vs 179 ± 49 min; p = 0.01), small bowel transit (289 ± 107 vs 224 ± 63 min; p = 0.001), colonic transit (2140, interquartile range [IQR] 1149-2799 min vs 1087, IQR 882-1650 min; p = 0.0001) and whole-gut transit time (2721, IQR 1196-3541 min vs 1475 (IQR 1278-2214) min; p CONCLUSIONS/INTERPRETATION: Pan-enteric prolongation of gastrointestinal transit times and a more acidic caecal pH, which may represent heightened caecal fermentation, are present in patients with type 1 diabetes. The potential implication of delayed gastrointestinal transit on the bioavailability of nutrition and on pharmacotherapeutic and glycaemic control warrants further investigation.TRIAL REGISTRATION: EUDRA CT: 2013-004375-12.

AIMS: To compare a novel index of parasympathetic tone, cardiac vagal tone, with established autonomic variables and to test the hypotheses that (1) cardiac vagal tone would be associated with established time and frequency domain measures of heart rate and (2) cardiac vagal tone would be lower in people with Type 1 diabetes than in a matched healthy cohort and lower still in people with established neuropathy.METHODS: Cardiac vagal tone is a validated cardiometrically derived index of parasympathetic tone. It is measured using a standard three-lead electrocardiogram which connects, via Bluetooth, to a smartphone application. A 5-min resting recording of cardiac vagal tone was undertaken and observational comparisons were made between 42 people with Type 1 diabetes and peripheral neuropathy and 23 without peripheral neuropathy and 65 healthy people. In those with neuropathy, 24-h heart rate variability values were compared with cardiac vagal tone. Correlations between cardiac vagal tone and clinical variables were also made.RESULTS: Cardiac vagal tone was lower in people with established neuropathy and Type 1 diabetes in comparison with healthy participants [median (interquartile range) linear vagal scale 3.4 (1.6-5.5 vs 7.0 (5.5-9.6); PCONCLUSIONS: Cardiac vagal tone represents a convenient, clinically relevant method, potentially facilitating the earlier identification of people with Type 1 diabetes who should undergo formal autonomic function testing. This article is protected by copyright. All rights reserved.

OBJECTIVE: The objective of this study was to elucidate whether the degree of autonomic modulation is associated with the degree of microvascular complications in patients with type 1 diabetes.METHODS: A total of 290 type 1 individuals with diabetes were randomly recruited during normal visits to outpatient clinics at 4 Danish hospitals. The degree of autonomic modulations was quantified by measuring heart rate variability (HRV) during passive spectral analysis and active tests (valsalva ratio [VT], response to standing [RT], and deep breathing [E:I]). To describe possible associations between severity of microvascular complications and measures of autonomic modulation, multivariate analysis was performed.RESULTS: After adjusting for diabetes duration, sex, age, pulse pressure, heart rate, and smoking, autonomic dysfunction remained significantly correlated with severity of retinopathy, nephropathy, and peripheral neuropathy in individuals with type 1 diabetes patients.CONCLUSIONS: Autonomic dysfunction is present in early stages of retinopathy, nephropathy, and peripheral neuropathy in patients with type 1 diabetes.

The objective was to identify the presence of cardiovascular autonomic neuropathy (CAN) in a cohort of individuals with diabetes in outpatient clinics from 4 different parts of Denmark and to explore the difference between type 1 and type 2 diabetes in relation to CAN. The DAN-Study is a Danish multicenter study focusing on diabetic autonomic neuropathy. Over a period of 12 months, 382 type 1 and 271 type 2 individuals with diabetes were tested for CAN. Patients were randomly recruited and tested during normal visits to outpatient clinics at 4 Danish hospitals. The presence of CAN was quantified by performing 3 cardiovascular reflex tests (response to standing, deep breathing, and valsalva). To describe possible associations, multivariate analysis with CAN as the dependent variable was performed. The prevalence of CAN was higher among patients with type 2 diabetes (35%) compared to patients with type 1 diabetes (25%). Multivariate analysis revealed significant associations between CAN and different risk markers in the 2 populations. In type 1 diabetes patients CAN was associated with microalbuminuria (P < .001), macroalbuminuria (P = .011), simplex retinopathy (P < .001), proliferative retinopathy (P < .001), and peripheral neuropathy (P = .041). Among type 2 diabetes patients CAN was independently associated with high pulse pressure (P < .01), BMI (P = .006), and smoking (P = .025). In this cross-sectional observational study CAN was independently associated with microvascular complication in type 1, whereas in type 2 CAN was associated with macrovascular risk factors. The objective was to identify the presence of cardiovascular autonomic neuropathy (CAN) in a cohort of individuals with diabetes in outpatient clinics from 4 different parts of Denmark and to explore the difference between type 1 and type 2 diabetes in relation to CAN. The DAN-Study is a Danish multicenter study focusing on diabetic autonomic neuropathy. Over a period of 12 months, 382 type 1 and 271 type 2 individuals with diabetes were tested for CAN. Patients were randomly recruited and tested during normal visits to outpatient clinics at 4 Danish hospitals. The presence of CAN was quantified by performing 3 cardiovascular reflex tests (response to standing, deep breathing, and valsalva). To describe possible associations, multivariate analysis with CAN as the dependent variable was performed. The prevalence of CAN was higher among patients with type 2 diabetes (35%) compared to patients with type 1 diabetes (25%). Multivariate analysis revealed significant associations between CAN and different risk markers in the 2 populations. In type 1 diabetes patients CAN was associated with microalbuminuria (P < .001), macroalbuminuria (P = .011), simplex retinopathy (P < .001), proliferative retinopathy (P < .001), and peripheral neuropathy (P = .041). Among type 2 diabetes patients CAN was independently associated with high pulse pressure (P < .01), BMI (P = .006), and smoking (P = .025). In this cross-sectional observational study CAN was independently associated with microvascular complication in type 1, whereas in type 2 CAN was associated with macrovascular risk factors.

Hoeck HC, Vestergaard P, Jakobsen PE, Laurberg P, Test of growth hormone secretion in adults: poor reproducibility of the insulin tolerance test. Eur J Endocrinol 1995;133:305–12. ISSN 0804–4643 The insulin tolerance test (ITT) is regarded as the most reliable provocative test in the diagnosis of growth hormone (GH) deficiency in adults. In the present study the test was evaluated by investigating the range of GH responses in normal adult males and females and the intra-individual reproducibility of the test. Sixteen healthy non-obese adults, eight males (median age 31.5 years) and eight females (median age 31.8 years) were tested twice with the ITT, with a minimum of 72 h between each test. The females were tested between day 3 and day 10 of their menstrual cycles. Adequate hypoglycemia was achieved in all cases with a median nadir blood glucose of 1.3 mmol/l (range 0.8–2.0). Growth hormone in serum was measured by immunoradiometric assay and low values were confirmed by a different assay. Median peak GH concentration responses to the ITT were: in males 27.9 μg/l, range 5.0–71.1 (test 1) and 30.5 μg/l, range 7.9–69.5 (test 2); and in females 9.0 μg/l, range 4.1–17.9 (test 1) and 8.4 μg/l, range 0.09–42.4 (test 2). The rise in GH concentration during the ITT was higher in males than in females. In the males, all stimulated GH values were ≥5.0 μg/l. In the females, four out of 16 tests gave values below 5.0 μg/l and in one test the GH value was around the detection limit of the assays. There was poor reproducibility during repeated testing, with no correlation between the results of the two tests. The results did not correlate to the magnitude of the hypoglycemia. The results of this study illustrate the complexity of the regulation of GH secretion and indicate that the ITT is less useful for diagnosing GH deficiency in adults than previously anticipated. The diagnosis of GH deficiency in adults and especially in adult females should not be based on the results of a single ITT alone. Hans C Hoeck, Department of Endocrinology, Aalborg Regional Hospital, Reberbansgade, DK-9000 Aalborg, Denmark

The insulin tolerance test (ITT) is widely accepted as the method of choice to evaluate GH secretion capacity in adults with hypothalamic-pituitary disorders. However, the test is not suitable in the elderly or in patients with cardiovascular disease or seizure disorders. In recent years alternatives to the ITT have been introduced. The purpose of the present study was to investigate the diagnostic outcome with the ITT, the pyridostigmine plus GHRH (PD + GHRH) test, the clonidine plus GHRH (CLO+GHRH) test, and insulin-like growth factor I (IGF-I) in an unselected group of patients with hypothalamic-pituitary disease. An evaluation of the reproducibility of the different stimulation tests was included in the study. Based on repeated testing with the various GH stimulation tests in healthy adult males and females, the lower limits of normality for the ITT, the PD+GHRH test, and the CLO+GHRH test were 3.92, 12.8, and 19.0, microg/L, respectively. A consecutive group of 26 unselected patients with hypothalamic-pituitary disorders, 13 males and 13 females (median age, 44 ys), were tested twice with all stimulation tests, except that only 10 patients were tested once with the CLO+GHRH test due to side-effects related to clonidine. The peak GH responses between test 1 and test 2 correlated significantly in both the ITT and the PD + GHRH test (P0.02), and no significant difference was observed in the median peak response to repeated testing. In addition, no sex difference was observed. The coefficients of variation (CV) were 96% (ITT) and 45% (PD + GHRH), but in the majority of patients low values were repeatedly low. The peak GH response was significantly higher during the PD+GHRH test than during the ITT (P = 0.008). In the 10 patients tested with the PD+GHRH and CLO+GHRH tests there was no significant difference in the peak GH response (P = 0.398). When the test specific cut-off values were used, no significant difference in diagnostic outcome was observed between the various tests (P0.3). In contrast, the diagnosis obtained with IGF-I differed significantly from all GH stimulation tests (P0.03). Twenty (77%) and 22 (85%) patients were diagnosed to be GH deficient with the ITT and the PD+GHRH test, respectively. Of the 14 patients with multiple pituitary failure (2 hormones affected), GH deficiency was present in more than 90% regardless of the type of stimulation test used. The IGF-I levels were only subnormal in 42% of the patients and did not correlate with the peak GH responses in any of the stimulation tests (P0.05). Except for 1 patient all patients with subnormal IGF-I were GH deficient in all stimulation tests. It is concluded that in patients with hypothalamic-pituitary disease and a normal IGF-I level 2 stimulation tests should be performed to establish a diagnosis of GH deficiency. In patients with a subnormal IGF-I value a single GH stimulation test should be sufficient to confirm the presence of GH deficiency.

In healthy adults, GH responses to provocative testing are variable between subjects. Information on the intra-subject variability is limited, despite the importance attached to GH stimulation tests in the diagnosis of GH deficiency. We have investigated and compared the variability of different GH stimulation tests in a group of healthy control subjects. In 16 healthy non-obese adults, two insulin tolerance tests (ITT) (0.15 IU/kg body weight i.v. and a fall in blood glucoseor = 2.2 mmol/l) two GHRH tests (1 microgram/kg body weight i.v.), and two clonidine (CLO) (300 micrograms p.o.) + GHRH (60 min later) tests were performed in the morning after an overnight fast. A pyridostigmine (PD) (120 mg p.o. 60 min before GHRH) + GHRH test was performed twice in an extended group of 31 healthy adult subjects. A wide range of GH responses was observed. Both during the ITT and the GHRH test, low values in the range generally recognized to reflect impairment of GH secretory status were encountered. The median (range) peak GH responses in tests 1 and 2 were: (a) ITT: 14.4 micrograms/l (4.1-71.1) and 14.0 micrograms/l (0.09-69.5), (b) GHRH test: 21.7 micrograms/l (0.71-56.2) and 18.4 micrograms/l (1.6-55.1); (c) CLO + GHRH test: 57.4 micrograms/l (22.9-209) and 65.8 micrograms/l (12.2-206); (d) PD + GHRH test: 36.5 micrograms/l (9.1-125) and 44.6 micrograms/l (6.3-101). The coefficients of variation (CV) were: 58% (ITT), 45% (GHRH), 46% (CLO + GHRH) and 26% (PD + GHRH). The peak GH responses were significantly different in all tests (CLO + GHRHPD + GHRHGHRHITT). In the individual subject, there was no systematic correlation between the peak GH responses in the different stimulation tests. In conclusion, we found that the stimulated GH responses were highly variable in all tests, and that the peak GH responses differed. Test results in patients should be evaluated against test-specific reference values, and caution is justified in the interpretation of low responses in a single test.

Previous studies have demonstrated poor reproducibility of growth hormone (GH) responses to insulin tolerance testing (ITT). In order to investigate whether this is a particular feature of GH secretion we studied the reproducibility of the GH and cortisol responses to ITT simultaneously and also compared the latter with the reproducibility during short ACTH testing (SAT). Eight normal men (age 26-50) and 8 normal women (age 27-45) underwent 2 ITT and 2 SAT. In the ITT no systematic differences were observed between test 1 and 2 concerning blood glucose, GH and cortisol before and after stimulation. Similar results were obtained for cortisol during SAT. During ITT reproducibility was good for the cortisol response (coefficient of variation [CV] 10%, no sex differences) but poor for the GH response (CV 41% in men, 104% in women). Reproducibility was good for the cortisol response in SAT (CV 12%, no sex differences). The peak cortisol values during ITT (mean 585, range 448-775 nmol/l) were significantly lower than in the 2 SAT (mean 723, range 486-918 nmol/l). We conclude that the GH response during testing is more variable than the cortisol response. This could account for some of the difficulties encountered in the diagnosis of GH deficiency in adults.